Why does a normal cell suddenly become a foreign for the body, breaking the rules, dividing recklessly, invading other tissues, usurping resources, and in some cases eventually killing the body in which it lives? To understand how and why cells rebel, we need to understand the normal functions of cell growth and reproduction. Research in cell biology, biochemistry, and molecular biology has provided astonishingly detailed information about the molecules and processes that allow cells to divide, grow, differentiate, and perform their essential functions.
This basic knowledge of cell biology has also led to practical discoveries about the mechanisms of cancer. Specific molecules that control the progression of a cell through the cell cycle regulate cell growth. An understanding of normal cell cycle processes and how those processes go awry provides key information about the mechanisms that trigger cancer. Loss of control of the cell cycle is one of the critical steps in the development of cancer.
Although cancer comprises at least 100 different diseases, all cancer cells share one important characteristic: they are abnormal cells in which the processes regulating normal cell division are disrupted. That is, cancer develops from changes that cause normal cells to acquire abnormal functions. These changes are often the result of inherited mutations or are induced by environmental factors such as UV light, X-rays, chemicals, tobacco products, and viruses.
All evidence suggests that most cancers are not the result of one single event or factor. Rather, around four to seven events are usually required for a normal cell to evolve through a series of premalignant stages into an invasive cancer. Often many years elapse between the initial event and the development of cancer. The development of molecular biological techniques may help in the diagnosis of potential cancers in the early stages, long before tumors are visible.
What is cancer?
Cancer results from a series of molecular events that fundamentally alter the normal properties of cells. In cancer cells, the normal control systems that prevent cell overgrowth and the invasion of other tissues are disabled. These altered cells divide and grow in the presence of signals that normally inhibit cell growth; therefore, they no longer require special signals to induce cell growth and division. As these cells grow, they develop new characteristics, including changes in cell structure, decreased cell adhesion, and production of new enzymes. These heritable changes allow the cell and its progeny to divide and grow, even in the presence of normal cells that typically inhibit the growth of nearby cells. Such changes allow the cancer cells to spread and invade other tissues. The abnormalities in cancer cells usually result from mutations in protein-encoding genes that regulate cell division.
Over time, more genes become mutated. This is often because the genes that make the proteins that normally repair DNA damage are themselves not functioning normally because they are also mutated. Consequently, mutations begin to increase in the cell, causing further abnormalities in that cell and the daughter cells. Some of these mutated cells die, but other alterations may give the abnormal cell a selective advantage that allows it to multiply much more rapidly than the normal cells. This enhanced growth describes most cancer cells, which have gained functions repressed in the normal, healthy cells. As long as these cells remain in their original location, they are considered benign; if they become invasive, they are considered malignant. Cancer cells in malignant tumors can often metastasize, sending cancer cells to distant sites in the body where new tumors may form.
Genetics of cancer
Alterations in the same gene are often associated with different forms of cancer. These malfunctioning genes can be broadly classified into three groups:
The first group, called proto-oncogenes, produces protein products that normally enhance cell division or inhibit normal cell death. The mutated forms of these genes are called oncogenes.
The second group, called tumor suppressors, makes proteins that normally prevent cell division or cause cell death.
The third group contains DNA repair genes, which help prevent mutations that lead to cancer.
Controlled cell growth is maintained by regulation of proto-oncogenes, which accelerate growth, and tumor suppressor genes, which slow cell growth. Mutations that produce oncogenes accelerate growth, while those that affect tumor suppressors prevent the normal inhibition of growth. In either case, uncontrolled cell growth occurs.
In normal cells, proto-oncogenes code for the proteins send a signal to the nucleus to stimulate cell division. These signaling proteins act in a series of steps called signal transduction cascade or pathway. This cascade includes a membrane receptor for the signal molecule, intermediary proteins that carry the signal through the cytoplasm and transcription factors in the nucleus that activate the genes for cell division. In each step of the pathway, one factor or protein activates the next; however, some factors can activate more than one protein in the cell. Oncogenes are altered versions of the proto-oncogenes that code for these signaling molecules. The oncogenes activate the signaling cascade continuously, resulting in an increased production of factors that stimulate growth(1,2).
An initial appearance of malignant transformation is represented by the disturbance of cell divizions. Normal cells grow and divide in accordance with the cell cycle.
Mutations in proto-oncogenes or in tumor suppressor genes allow a cancerous cell to grow and divide without the normal controls imposed by the cell cycle. The major events in the cell cycle are described in Figure 1.
The cell cycle is an ordered process of events that occurs in four stages. During the two gap phases, G1 and G2, the cell is actively metabolizing but not dividing. In S (synthesis) phase the chromosomes duplicate as a result of DNA replication. During the M (mitosis) phase, the chromosomes separate in the nucleus and the division of the cytoplasm (cytokinesis) occurs.
There are checkpoints in the cycle at the end of G1 and G2 that can prevent the cell from entering the S or M phases of the cycle. Cells that are not in the process of diving are in the G0 stage, which includes most adult cells.
Several proteins control the timing of the events in the cell cycle, which is tightly regulated to ensure that cells divide only when necessary. The loss of this regulation is the hallmark of cancer(3).
The major control switches of the cell cycle are cyclin-dependent kinases. Each cyclin-dependent kinase forms a complex with a particular cyclin, a protein that binds and activates the cyclin-dependent kinase. The kinase part of the complex is an enzyme that adds a phosphate to various proteins required for progression of a cell through the cycle. These added phosphates alter the structure of the protein and can activate or inactivate the protein, depending on its function. There are specific cyclin-dependent kinase/cyclin complexes at the entry points into the G1, S, and M phases of the cell cycle, as well as additional factors that help prepare the cell to enter S phase and M phase.
Cancer cells do not stop dividing, so what stops a normal cell from dividing? In terms of cell division, normal cells differ from cancer cells in at least four ways:
Normal cells require external growth factors to divide. When synthesis of these growth factors is inhibited by normal cell regulation, the cells stop dividing. Cancer cells have lost the need for positive growth factors, so they divide whether or not these factors are present. Consequently, they do not behave as part of the tissue – they have become independent cells.
Normal cells show contact inhibition; that is, they respond to contact with other cells by ceasing cell division. Therefore, cells can divide to fill in a gap, but they stop dividing as soon as there are enough cells to fill the gap. This characteristic is lost in cancer cells, which continue to grow after they touch other cells, causing a large mass of cells to form.
Normal cells age and die, and are replaced in a controlled and orderly manner by new cells. Apoptosis is the normal, programmed death of cells. Normal cells can divide only about fifty times before they die. This is related to their ability to replicate DNA only a limited number of times. Each time the chromosome replicates, the ends (telomeres) shorten. In growing cells, the enzyme telomerase replaces these lost ends. Adult cells lack telomerase, limiting the number of times the cell can divide. However, telomerase is activated in cancer cells, allowing an unlimited number of cell divisions.
Normal cells cease to divide and die when there is DNA damage or when cell division is abnormal. Cancer cells continue to divide, even when there is a large amount of damage to DNA or when the cells are abnormal. These progeny cancer cells contain the abnormal DNA; so, as the cancer cells continue to divide, they accumulate even more damaged DNA.
There is also strong evidence that the excessive addition of methyl groups to genes involved in the cell cycle, DNA repair and apoptosis is characteristic of some cancers(4,5).
There may be multiple mechanisms leading to the development of cancer. This further complicates the difficult task of determining what causes cancer. Cancer cells behave as independent cells, growing without control to form tumors. Tumors grow in a series of steps. The first step is hyperplasia, meaning that there are too many cells resulting from uncontrolled cell division. These cells appear normal, but changes have occurred that result in some loss of control of growth. The second step is dysplasia, resulting from further growth, accompanied by abnormal changes to the cells. The third step requires additional changes, which result in cells that are even more abnormal and can now spread over a wider area of tissue. These cells begin to lose their original function; such cells are called anaplastic. At this stage, because the tumor is still contained within its original location (called in situ) and is not invasive, it is not considered malignant - it is potentially malignant. The last step occurs when the cells in the tumor metastasize, which means that they can invade surrounding tissue, including the bloodstream, and spread to other locations. This is the most serious type of tumor, but not all tumors progress to this point. Non-invasive tumors are said to be benign. The type of tumor that forms depends on the type of cell that was initially altered. There are five types of tumors:
Carcinomas result from altered epithelial cells, which cover the surface of our skin and internal organs. Most cancers are carcinomas.
Sarcomas result from changes in muscle, bone, fat, or connective tissue.
Leukemia results from malignant white blood cells.
Lymphoma is a cancer of the lymphatic system cells that derive from bone marrow.
Myelomas are cancers of specialized white blood cells that make antibodies.
Although tumor cells are no longer dependent on the control mechanisms that govern normal cells, they still require nutrients and oxygen in order to grow. All living tissues are amply supplied with capillary vessels, which bring nutrients and oxygen to every cell. As tumors enlarge, the cells in the center no longer receive nutrients from the normal blood vessels. To provide a blood supply for all the cells in the tumor, it must form new blood vessels to supply the cells in the center with nutrients and oxygen. In a process called angiogenesis, tumor cells make growth factors which induce formation of new capillary blood vessels. The cells of the blood vessels that divide to make new capillary vessels are inactive in normal tissue; however, tumors make angiogenic factors, which activate these blood vessel cells to divide. Without the additional blood supplied by angiogenesis, tumors can grow no larger than about half a millimeter. Without a blood supply, tumor cells also cannot spread, or metastasize, to new tissues. Tumor cells can cross through the walls of the capillary blood vessel at a rate of about one million cells per day. However, not all cells in a tumor are angiogenic. Both angiogenic and non-angiogenic cells in a tumor cross into blood vessels and spread; however, non-angiogenic cells give rise to dormant tumors when they grow in other locations. In contrast, the angiogenic cells quickly establish themselves in new locations by growing and producing new blood vessels, resulting in rapid growth of the tumor. Dormant tumors are those that do not have blood vessels; they are generally less than half a millimeter in diameter. Several autopsy studies in which trauma victims were examined for such very small tumors revealed that 39% of women aged forty to fifty have very small breast tumors, while 46% of men aged sixty to seventy have very small prostate tumors. Amazingly, 98% of the people aged fifty to seventy have very small thyroid tumors. However, for those age groups in the general population, the incidence of these particular cancers is only one-tenth of a percent (thyroid) or one percent (breast or prostate cancer). The conclusion is that the incidence of dormant tumors is very high compared to the incidence of cancer. Therefore, angiogenesis is critical for the progression of dormant tumors into cancer.